The present work continues prior investigation of insulin receptors on circulating cells in patients with insulin resistance and diabetes mellitus. Insulin receptors are evaluated for their ability to bind insulin and to act as tyrosine-specific protein kinases. We have specifically studied two individual patients: one with a Type A form of insulin resistance that binds insulin normally but has reduced tyrosine- kinase activity, and the second, a patient with a Rabson-Mendenhall Syndrome, who has a severe defect in insulin binding. In addition, we have continued to study patients with autoantibodies to the insulin receptor associated with insulin resistance. GRANT-Z01DK47018 The insulin-like growth factor family comprises two peptides, (insulin- like growth factor-I and insulin-like growth factor-II), six binding proteins, (insulin-like growth factor binding protein 1-6) and two receptors. They are widely expressed and play an essential role in the growth and development of all tissues, as well as in the normal functioning of differentiated tissues. The gene for insulin-like growth factor-I is very complex and its expression is regulated at multiple levels. Its action may be modulated by the insulin-like growth factor binding proteins either by enhancement or inhibition. Insulin-like growth factor-I and the insulin-like growth factor binding proteins are important in development of the ovary and in particular in granulosa cell maturation and steroidogenesis. Cancer cells express the insulin-like growth factor binding proteins in different combinations and in response to different factors. These insulin-like growth factor binding proteins can modulate the effect of insulin-like growth factor-I on cancer cell proliferation. Diabetic kidney disease is associated with hemodynamic changes which are most probable induced by insulin-like growth factor-I which accumulates in the kidney due to increased kidney insulin-like growth factor binding protein-1 expression. Finally, the Insulin-like growth factor system apparently plays a significant role in splenic growth and development and therefore may be an important factor in immune responsiveness.